DOCSLIB.ORG

Structural Basis for the Enhanced Anti-Diabetic Efficacy Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Structural Basis for the Enhanced Anti-Diabetic Efficacy Of www.nature.com/scientificreports OPEN Structural Basis for the Enhanced Anti-Diabetic Efcacy of Lobeglitazone on PPARγ Received: 9 October 2017 Jun Young Jang 1, Hwan Bae2, Yong Jae Lee3, Young Il Choi3, Hyun-Jung Kim4, Accepted: 4 December 2017 Seung Bum Park 2, Se Won Suh2, Sang Wan Kim 5 & Byung Woo Han 1 Published: xx xx xxxx Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte diferentiation, insulin resistance, and infammation. Here, we report the crystal structures of PPARγ in complex with lobeglitazone, a novel PPARγ agonist, and with rosiglitazone for comparison. The thiazolidinedione (TZD) moiety of lobeglitazone occupies the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) in ligand-binding domain as the TZD moiety of rosiglitazone does. However, the elongated p-methoxyphenol moiety of lobeglitazone interacts with the hydrophobic pocket near the alternate binding site of PPARγ. The extended interaction of lobeglitazone with the hydrophobic pocket enhances its binding afnity and could afect the cyclin- dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). Lobeglitazone inhibited the phosphorylation of PPARγ at Ser245 in a dose-dependent manner and exhibited a better inhibitory efect on Ser245 phosphorylation than rosiglitazone did. Our study provides new structural insights into the PPARγ regulation by TZD drugs and could be useful for the discovery of new PPARγ ligands as an anti-diabetic drug, minimizing known side efects. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by a group of ligands belonging to the thyroid/retinoid family (class II) of nuclear receptors1. PPARs regulate the transcription of target genes through heterodimerization with retinoid X receptors (RXRs) and binding to cognate peroxisome pro- liferator response elements (PPREs)2. PPARs, known as “lipid-sensing” receptors, are present in three subtypes (PPARα, PPARγ, and PPARδ/β) and regulate lipid and glucose homeostasis3. PPARγ is highly expressed in adi- pocytes and is also expressed in epithelial cells and macrophages. It plays important roles in adipocyte diferenti- ation, insulin resistance, and atherosclerosis4. PPARγ has a remarkably larger ligand-binding pocket (LBP) than other nuclear receptors5 and is known to be activated by a wide range of endogenous ligands and synthetic ligands. Although the physiological ligand of PPARγ has not been clearly elucidated yet, the endogenous PPARγ ligands reported so far include polyun- saturated fatty acids6, oxidized fatty acids7, nitrated fatty acids8, lysophospholipids9, and prostanoids such as 15-deoxy-Δ12,14-prostaglandin J210. Synthetic ligands of PPARγ can be classifed as full agonists, partial ago- nists, and antagonists. When full agonists bind to PPARγ, the activation function-2 (AF-2) helix (i.e., helix H12) changes its conformation and PPARγ recruits coactivator to induce adipogenesis and insulin sensitization11,12. PPARγ is also activated by partial agonists. However, partial agonists stabilize PPARγ ligand-binding domain (LBD) in a distinct manner compared with full agonists. Partial agonists stabilize the β-sheet region (β1, β2, and β4, and helix H3 preferentially, but leave AF-2 helix in a very dynamic state13. Antagonists exhibit high afnity but do not activate PPARγ, suggesting that the conformational change in AF-2 helix is not sufcient to allow coacti- vator binding or AF-2 helix exists in its inactive form14. 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. 2Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 08826, Republic of Korea. 3CKD Research Institute, Chong Kun Dang Pharmaceutical Corporation, Yongin, 16995, Republic of Korea. 4College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea. 5College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea. Correspondence and requests for materials should be addressed to S.W.K. (email: [email protected]) or B.W.H. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:31 | DOI:10.1038/s41598-017-18274-1 1 www.nature.com/scientificreports/ Figure 1. Chemical structures of lobeglitazone, rosiglitazone, and pioglitazone. PPARγ is a good therapeutic target for type 2 diabetes mellitus. When the thiazolidinedione (TZD) class of anti-diabetic drugs was frst reported in 1980s15, the molecular basis of TZD drugs was unclear. In 1990s, TZD drugs were found to bind to PPARγ16, and as mentioned above, various synthetic ligands for PPARγ have been developed so far. Full agonists such as TZD drugs are efective in treating type 2 diabetes mellitus, but adverse efects have been problematic, including fuid retention, edema, bone loss, and weight gain17. Te mechanism underlying the anti-diabetic efects of TZD drugs and their side efects has not been well understood. Recently, Choi et al. reported that the phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering) by cyclin-dependent kinase 5 (Cdk5) neither activates nor inhibits general transcriptional activity of PPARγ, but it changes the expression of specifc genes such as adiponectin and adipsin that are linked to insu- lin sensitivity18. TZD drugs have been known to strongly regulate both the Cdk5-mediated phosphorylation of PPARγ and the expression of PPARγ target genes18. Recent study has also revealed that the alternate binding site extending from the third arm of the known LBP of PPARγ could afect the phosphorylation of PPARγ at Ser24519. Tus, many researchers are trying to develop synthetic ligands that selectively inhibit the Cdk5-mediated phos- phorylation of PPARγ without classical transcriptional agonism20,21. Lobeglitazone (CKD-501; Chong Kun Dang Pharmaceutical Corp., Seoul, Republic of Korea) is an anti-diabetic drug of the TZD class known as a potent PPARγ agonist, and has been used in the treatment of type 2 diabetes mellitus22. Lobeglitazone is structurally similar to two well-known TZD drugs, rosiglitazone and pioglitazone, and was synthesized from the rosiglitazone backbone by substitution of the pyrimidine moiety for the pyridine part of rosiglitazone followed by addition of the p-methoxyphenol functional group at 4-position of the pyrimidine moiety (Fig. 1). Lobeglitazone showed better biological activities than known reference compounds (rosiglitazone and pioglitazone). Compared with rosiglitazone, lobeglitazone showed 100 times increased efcacy in the triglyceride accumulation experiments in 3T3-L1 cells and 2.4-fold and over 8-fold increased efcacies in the glucose and triglyceride lowering experiments in KKAy mice, respectively23. To our surprise, rosiglitazone and pioglitazone exhibit diferent clinical adverse events, which implies that slight changes in receptor-ligand interactions can cause signifcant pharmacological diferences in TZD drugs13. Tus, studies of PPARγ-ligand complex structures are cru- cial to better understand the mechanism of PPARγ modulation and it is also true with a more potent anti-diabetic drug, lobeglitazone. To elucidate a structural basis for understanding activities of lobeglitazone, we determined the crystal structure of PPARγ LBD in complex with lobeglitazone. For exact comparison of binding modes of lobeglitazone and rosiglitazone, we also determined the crystal structure of PPARγ LBD in complex with rosigl- itazone. Te overall binding mode of lobeglitazone to PPARγ LBD is very similar to that of rosiglitazone except the elongated p-methoxyphenol group of lobeglitazone. Notably, the elongated p-methoxyphenol group occupies the hydrophobic pocket near the alternate binding site of PPARγ. Lobeglitazone also blocked the Cdk5-mediated phosphorylation of PPARγ at Ser245 more potently than rosiglitazone did in vitro. Our results enhance the current understanding of PPARγ regulation by TZD drugs more in detail. Results Overall structure of lobeglitazone-bound PPARγ LBD and structural comparisons. To gain fur- ther insight on the binding mode of lobeglitazone, we solved the crystal structure of PPARγ LBD in complex with lobeglitazone in the presence of a peptide derived from the human steroid receptor coactivator-1 (SRC-1) coactivator protein at 2.15 Å resolution, using X-ray crystallography. For a comparative study, we have also deter- mined the rosiglitazone-bound structure of PPARγ LBD in the presence of the SRC-1 coactivator peptide. Te SCIENTIFIC REPORTS | (2018) 8:31 | DOI:10.1038/s41598-017-18274-1 2 www.nature.com/scientificreports/ Figure 2. Overall structures of PPARγ LBD in complex with lobeglitazone and with rosiglitazone. Lobeglitazone-bound and rosiglitazone-bound PPARγ LBD structures are superimposed and colored in salmon and yellow orange, respectively, all of which include the SRC-1 coactivator peptide colored same with bound PPARγ LBD structures. Lobeglitazone and rosiglitazone are represented as a stick model in green and pale cyan, respectively. Ser245 (PPARγ1 numbering; Ser273 in PPARγ2 numbering) is the Cdk5-mediated phosphorylation site, shown by red sticks. Regions with RMSD 2.0 Å and bigger are indicated with blue dashed circles. Overall structures are shown in stereo view. structures adopt the canonical fold of general nuclear receptors1,
Load more

Recommended publications
  • The Antidiabetic Drug Lobeglitazone Has the Potential to Inhibit PTP1B T Activity ⁎ Ruth F
    Bioorganic Chemistry 100 (2020) 103927 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B T activity ⁎ Ruth F. Rochaa, Tiago Rodriguesc, Angela C.O. Menegattia,b, , Gonçalo J.L. Bernardesc,d, Hernán Terenzia a Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil b Universidade Federal do Piauí, CPCE, 64900-000 Bom Jesus, PI, Brazil c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal d Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK ARTICLE INFO ABSTRACT Keywords: Protein tyrosine phosphatase 1B (PTP1B) is considered a potential therapeutic target for the treatment of type 2 Thiazolidinediones diabetes mellitus (T2DM), since this enzyme plays a significant role to down-regulate insulin and leptin sig- Lobeglitazone nalling and its over expression has been implicated in the development of insulin resistance, T2DM and obesity. PPAR-γ Some thiazolidinediones (TZD) derivatives have been reported as promising PTP1B inhibitors with anti hy- PTP1B perglycemic effects. Recently, lobeglitazone, a new TZD, was described as an antidiabetic drug that targetsthe Non-competitive inhibitors PPAR-γ (peroxisome γ proliferator-activated receptor) pathway, but no information on its effects on PTP1B have been reported to date. We investigated the effects of lobeglitazone on PTP1B activity in vitro. Surprisingly, lobeglitazone led to moderate inhibition on PTP1B (IC50 42.8 ± 3.8 µM) activity and to a non-competitive reversible mechanism of action.
    [Show full text]
  • Insulin Aspart Sanofi, If It Is Coloured Or It Has Solid Pieces in It
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Insulin aspart Sanofi 100 units/ml solution for injection in vial Insulin aspart Sanofi 100 units/ml solution for injection in cartridge Insulin aspart Sanofi 100 units/ml solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml solution contains 100 units insulin aspart* (equivalent to 3.5 mg). Insulin aspart Sanofi 100 units/ml solution for injection in vial Each vial contains 10 ml equivalent to 1,000 units insulin aspart. Insulin aspart Sanofi 100 units/ml solution for injection in cartridge Each cartridge contains 3 ml equivalent to 300 units insulin aspart. Insulin aspart Sanofi 100 units/ml solution for injection in pre-filled pen Each pre-filled pen contains 3 ml equivalent to 300 units insulin aspart. Each pre-filled pen delivers 1-80 units in steps of 1 unit. *produced in Escherichia coli by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear, colourless, aqueous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Insulin aspart Sanofi is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above. 4.2 Posology and method of administration Posology The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.
    [Show full text]
  • Dualism of Peroxisome Proliferator-Activated Receptor Α/Γ: a Potent Clincher in Insulin Resistance
    AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues.
    [Show full text]
  • Comparative Transcriptional Network Modeling of Three PPAR-A/C Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes
    Comparative Transcriptional Network Modeling of Three PPAR-a/c Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes Rene´e Deehan1, Pia Maerz-Weiss2, Natalie L. Catlett1, Guido Steiner2, Ben Wong1, Matthew B. Wright2*, Gil Blander1¤a, Keith O. Elliston1¤b, William Ladd1, Maria Bobadilla2, Jacques Mizrahi2, Carolina Haefliger2, Alan Edgar{2 1 Selventa, Cambridge, Massachusetts, United States of America, 2 F. Hoffmann-La Roche AG, Basel, Switzerland Abstract Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-a/c agonist, aleglitazar, with tesaglitazar (a dual PPAR-a/c agonist) or a combination of pioglitazone (Pio; PPAR-c agonist) and fenofibrate (Feno; PPAR-a agonist) in human hepatocytes. Methods and Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-a signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect.
    [Show full text]
  • Corporate Presentation June 2019 Disclaimer
    Corporate Presentation June 2019 Disclaimer Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward- looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. 2 Well Diversified Mid-to-Late Stage Metabolic Pipeline for Large Market Opportunities Global partnerships secured for late stage clinical program in type 2 diabetes • Imeglimin: First in class oral drug candidate targeting
    [Show full text]
  • CDR Clinical Review Report for Soliqua
    CADTH COMMON DRUG REVIEW Clinical Review Report Insulin glargine and lixisenatide injection (Soliqua) (Sanofi-Aventis) Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin. Service Line: CADTH Common Drug Review Version: Final (with redactions) Publication Date: January 2019 Report Length: 118 Pages Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document.
    [Show full text]
  • Lobeglitazone
    2013 International Conference on Diabetes and Metabolism Lobeglitazone, A Novel PPAR-γ agonist with balanced efficacy and safety Kim, Sin Gon. MD, PhD. Professor, Division of Endocrinology and Metabolism Department of Internal Medicine, Korea University College of Medicine. Disclosure of Financial Relationships This symposium is sponsored by Chong Kun Dang Pharmaceutical Corp. I have received lecture and consultation fees from Chong Kun Dang. Pros & Cons of PPAR-γ agonist Pros Cons • Good glucose lowering • Adverse effects • Durability (ADOPT) (edema, weight gain, • Insulin sensitizing CHF, fracture or rare effects (especially in MS, macular edema etc) NAFLD, PCOS etc) • Possible safety issues • Prevention of new- (risk of MI? – Rosi or onset diabetes (DREAM, bladder cancer? - Pio) ACT-NOW) • LessSo, hypoglycemiathere is a need to develop PPAR-γ • Few GI troubles agonist• Outcome with data balanced efficacy and safety (PROactive) Insulin Sensitizers : Several Issues Rosi, Peak sale ($3.3 billion) DREAM Dr. Nissen Dr. Nissen ADOPT META analysis BARI-2D (5,8) Rosi, lipid profiles RECORD 1994 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Tro out d/t FDA, All diabetes hepatotoxicity drug CV safety Rosi (5) FDA, Black box Rosi, Rosi , CV safety warning - REMS in USA = no evidence - Europe out Pio (7) PIO, bladder cancer CKD 501 Lobeglitazone 2000.6-2004.6 2004.11-2007.1 2007.3-2008.10 2009.11-2011.04 Discovery& Preclinical study Phase I Phase II Phase III Developmental Strategy Efficacy • PPAR activity Discovery & Preclinical study • In vitro & vivo efficacy • Potent efficacy 2000.06 - 2004.06 Phase I 2004.11 - 2007.01 • In vitro screening • Repeated dose toxicity • Metabolites • Geno toxicity • Phase II CYP 450 • Reproductive toxicity 2007.03 - 2008.10 • DDI • Carcinogenic toxicity ADME Phase III Safety 2009.11 - 2011.04 CV Safety / (Bladder) Cancer / Liver Toxicity / Bone loss Lobeglitazone (Duvie) 1.
    [Show full text]
  • Title: Combination of Pparg Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas
    Author Manuscript Published OnlineFirst on September 3, 2019; DOI: 10.1158/1078-0432.CCR-19-0976 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Combination of PPARg agonist pioglitazone and trabectedin induce adipocyte differentiation to overcome trabectedin resistance in myxoid liposarcomas Roberta Frapolli1, Ezia Bello1, Marianna Ponzo1, Ilaria Craparotta2, Laura Mannarino2, Sara Ballabio2, Sergio Marchini2, Laura Carrassa3, Paolo Ubezio4, Luca Porcu5, Silvia Brich6, Roberta Sanfilippo7, Paolo Giovanni Casali7, Alessandro Gronchi8, Silvana Pilotti6, and Maurizio D’Incalci9*. 1 Unit of Preclinical Experimental Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 2 Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 3Unit of DNA repair, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 4 Unit of Biophysics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 5 Unit of Methodological Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 6Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 7 Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 8 Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 9 Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. Running title: Pioglitazone - trabectedin in myxoid liposarcomas. Keywords: Myxoid liposarcoma, trabectedin resistance, PPAR agonist, and patient-derived xenograft. Additional information: Financial support: This work was supported by the Italian Association for Cancer Research grant to M.D.
    [Show full text]
  • AVANDIA (Rosiglitazone Maleate Tablets), for Oral Use Ischemic Cardiovascular (CV) Events Relative to Placebo, Not Confirmed in Initial U.S
    HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ----------------------- These highlights do not include all the information needed to use • Fluid retention, which may exacerbate or lead to heart failure, may occur. AVANDIA safely and effectively. See full prescribing information for Combination use with insulin and use in congestive heart failure NYHA AVANDIA. Class I and II may increase risk of other cardiovascular effects. (5.1) • Meta-analysis of 52 mostly short-term trials suggested a potential risk of AVANDIA (rosiglitazone maleate tablets), for oral use ischemic cardiovascular (CV) events relative to placebo, not confirmed in Initial U.S. Approval: 1999 a long-term CV outcome trial versus metformin or sulfonylurea. (5.2) • Dose-related edema (5.3) and weight gain (5.4) may occur. WARNING: CONGESTIVE HEART FAILURE • Measure liver enzymes prior to initiation and periodically thereafter. Do See full prescribing information for complete boxed warning. not initiate therapy in patients with increased baseline liver enzyme levels ● Thiazolidinediones, including rosiglitazone, cause or exacerbate (ALT >2.5X upper limit of normal). Discontinue therapy if ALT levels congestive heart failure in some patients (5.1). After initiation of remain >3X the upper limit of normal or if jaundice is observed. (5.5) AVANDIA, and after dose increases, observe patients carefully for signs • Macular edema has been reported. (5.6) and symptoms of heart failure (including excessive, rapid weight gain; • Increased incidence of bone fracture was observed in long-term trials. dyspnea; and/or edema). If these signs and symptoms develop, the heart (5.7) failure should be managed according to current standards of care.
    [Show full text]
  • Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes: a Meta-Analysis
    Online Supplementary Content Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. doi:10.1001/jama.2016.9400. eMethods. Summary of Statistical Analysis eTable 1. Search Strategies eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin Plus Sulfonylurea eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 7. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea eTable 8. Estimated Global Inconsistency in Networks of Outcomes eTable 9. Estimated Heterogeneity in Networks eTable 10. Definitions of Treatment Failure Outcome eTable 11. Contributions of Direct Evidence to the Networks of Treatments eTable 12. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes Given as Monotherapy eTable 13. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes When Used in Dual Therapy (in Addition to Metformin) eTable 14. Network Meta-analysis Estimates of Comparative Treatment Effects for Drug Classes Given as Triple Therapy eTable 15. Meta-regression Analyses for Drug Classes Given as Monotherapy (Compared With Metformin) eTable 16. Subgroup Analyses of Individual Sulfonylurea Drugs (as Monotherapy) on Hypoglycemia eTable 17.
    [Show full text]
  • The Effect of Rosiglitazone on Overweight Subjects with Type 1 Diabetes
    Clinical Care/Education/Nutrition ORIGINAL ARTICLE The Effect of Rosiglitazone on Overweight Subjects With Type 1 Diabetes SUZANNE M. STROWIG, MSN, RN the potentially serious consequences of PHILIP RASKIN, MD excessive weight gain and insulin- induced hypoglycemia, investigators con- tinue to search for treatments that address both the treatment of insulin deficiency as well as other metabolic abnormalities that OBJECTIVE — To evaluate the safety and effectiveness of rosiglitazone in the treatment of are associated with diabetes (5). overweight subjects with type 1 diabetes. Insulin resistance, a metabolic abnor- mality common in type 2 diabetes, ap- RESEARCH DESIGN AND METHODS — A total of 50 adult type 1 diabetic subjects 2 pears to be present in individuals with with a baseline BMI Ն27 kg/m were randomly assigned in a double-blind fashion to take insulin and placebo (n ϭ 25) or insulin and rosiglitazone 4 mg twice daily (n ϭ 25) for a period of 8 type 1 diabetes, as well. Although insulin months. Insulin regimen and dosage were modified in all subjects to achieve near-normal resistance in type 2 diabetes is generally glycemic control. associated with obesity, hypertension, dyslipidemia, and other metabolic disor- RESULTS — Both groups experienced a significant reduction in HbA1c (A1C) level (rosigli- ders, studies have shown that overweight tazone: 7.9 Ϯ 1.3 to 6.9 Ϯ 0.7%, P Ͻ 0.0001; placebo: 7.7 Ϯ 0.8 to 7.0 Ϯ 0.9%, P ϭ 0.002) and as well as normal-weight adults with type a significant increase in weight (rosiglitazone: 97.2 Ϯ 11.8 to 100.6 Ϯ 16.0 kg, P ϭ 0.008; 1 diabetes can have peripheral and he- Ϯ Ϯ ϭ ϭ placebo: 96.4 12.2 to 99.1 15.0, P 0.016).
    [Show full text]
  • AVANDIA® (Rosiglitazone Maleate) Tablets
    PRESCRIBING INFORMATION AVANDIA® (rosiglitazone maleate) Tablets WARNING: CONGESTIVE HEART FAILURE ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered. ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) DESCRIPTION AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). AVANDIA improves glycemic control while reducing circulating insulin levels. Pharmacological studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is: The molecular formula is C18H19N3O3S•C4H4O4.
    [Show full text]